Advances Towards the Synthesis of Aporphine Alkaloids: C‐Ring Formation via Approaches Based on One‐ and Two‐Bond Disconnections

Abstract

Aporphine compounds constitute a class of substances with important pharmacological properties, including anticancer, antiviral, anti-HIV, anti-inflammatory, and leishmanicidal activities. Consequently, several strategies to obtain the aporphine core have been reported. Herein this review, we provide an overview of two relevant approaches used to construct the Cring in the synthetic routes developed. The first approach, which is based on a one-bond disconnection, allows C-ring formation using a 1-benzyl-1,2,3,4-tetrahydroisoquinoline intermediate (mainly) employing cyclization reactions catalyzed by metals or promoted by light. The second approach, which is derived from a two-bond disconnection, leads to C-ring formation via a sequence of reactions starting with [4 + 2] cycloadditions. Through these approaches, aporphinoids with a diverse range of substitution patterns and biological activities can be synthesized.

Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome

“…Apomorphine has two hydroxy groups (-OH) at positions 10 and 11 of its aporphine framework, so to verify which has the essential anti-cell death effect, we produced three similar derivatives: D29, D30, and D31. D29 is a precursor of apomorphine in the synthesis of apomorphine using o-silyl aryl triflate; however, its cytotoxic activity against cancer cells has not been reported 13 .…”

Total Synthesis of Aporphine Alkaloids via Benzyne Chemistry: Progress Towards a Late‐Stage Enantioselective Hydrogenation and Neuroprotective Activity Evaluations

“…Currently, two well‐established synthetic approaches to produce aporphinoids are available [1a,8–17] . The first strategy is based on biosynthetic routes and employs 1‐benzyl‐1,2,3,4‐tetrahydroisoquinoline intermediates for the C ring formation through several transformations: 1) phenolic couplings, [8,10] 2) Pschorr reaction, [9] 3) nonphenolic couplings, [8,11] 4) photochemical reactions, [12] 5) acid‐catalyzed reactions, [13] and 6) palladium‐catalyzed reactions [14] .…”